As the first therapeutic antibody, OKT-3,  launched in 1986, more and more therapeutic monoclonal antibodies(mAb) have entered the clinical stage and gone to the market. The therapeutic monoclonal  antibodies have become an effective targeted treatment for cancer, viral  infection, and autoimmune diseases. However, in cancer and autoimmune diseases,  multiple signal pathways need to be blocked simultaneously to avoid  compensatory effects. In viral infections, similarly, we use cocktail therapy to avoid ineffectiveness caused by the viral mutation. On the other hand, mAb  can only bind to a single target and exert a single biological activity. They  are not able to satisfy those requirements mentioned above. With the  advancement of antibody engineering technology, bispecific antibodies and  antibody-drug conjugates will be the next wave of antibody research.

 Bispecific  antibody

Bispecific antibodies can simultaneously  bind to two different epitopes or antigens to block/activate dual target  signaling pathways. This induces immune cells to better kill tumor cells due to  the synergistic effects. Therefore, a bispecific antibody is better than a mAb  or even a combination of two mAbs. Besides cancers, bispecific antibodies are  also used in the treatment of osteoporosis, hemophilia, and autoimmune  diseases.

     Figure 1 Structures of bispecific  antibodies and the mechanism of action

Bispecific antibodies draw more and more  attention these years. So far, more than 100 bispecific antibody structures  were reported. More than 150 bispecific antibodies are in the clinical stage,  and more than 400 are in the preclinical research. Bispecific antibodies can be  divided into three categories based on their structures:

     1. the structures without Fc fragment (such  as Blincyto);
     2. the asymmetric structures with Fc  fragment;
     3. the symmetrical structures with Fc  fragment. (The binding epitope of the second antibody is fused to the heavy or  light chain of the first antibody to recognize a second target. scFv is the  most common one.)
 

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Antibody-Drug  Conjugate

(ADC) is a conjugation of a highly targeted antibody drug and a  powerful chemo drug. ADC can accurately deliver drugs into tumor cells to avoid  the killing of normal cells, thereby reducing the adverse effects of chemo  drugs. The first ADC drug, Mylotarg, was approved as early as 2000. However,  the outbreak of ADC research didn’t come until 2019. So far, there are 9 drugs  on the market, 5 of which were approved simply in 2019. According to the  forecasts of Evaluate Pharma and BCG, the market size of ADC is expected to  reach US$12.9 billion globally in 2024.

Figure 3 Classical ADC mode of action  (Chinese antibody society)

ADC drugs are mainly used in cancer  treatments. Due to a limited number of antigens on the surface of tumor cells,  the amount of drug delivered to tumor cells is relatively low. Therefore, the  choice of target antigens is crucial. The criteria for ADC target selection are  the same as for monoclonal antibody drugs. Ideally, the target is required to  be only on the surface of tumor cells with limited or no expression in normal  tissues. Meanwhile, it can have a certain rate of endocytosis and a suitable  route of endocytic transport.

The tumor-killing effects of ADC drugs  mainly rely on chemo drug molecules. The target is to bind the antibody and  bring the chemo drug into the cancer cells by endocytosis. Whether or not the  target has a biological effect is not critical. Therefore, compared with mAbs,  ADC drugs have more target options.

     Figure  4 ADC targets for solid tumors

With a strong team of scientists, ACROBiosystems also  provides high-quality  integrated SPR&BLI analytical services. ACRO has served and  collaborated with more than 200 customers from academia and industry. Our work  supported multiple antibody drugs IND applications.
     
     
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Antibody binding with target protein

Herceptin (Trastuzumab) captured on CM5 chip via anti-human IgG Fc antibodies surface, can bind Human Her2, His Tag (Cat. No. HE2-H5225) with an affinity constant of 1.07 nM as determined in a SPR assay.

BsAb binding with Fc receptor protein

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Reference：
     Development of bispecific antibodies in  China: overview and prospects.
     Biology drives the discovery of bispecific antibodies  as innovative therapeutics.
     British Journal of Cancer, 2016